ABSTRACT The long-term objective of this research proposal is to focus on the functional role of chemokines and chemokine receptors in disease, protection, and repair in two well-established models of CNS disease: infection of susceptible mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) and experimental autoimmune encephalomyelitis (EAE). In both models, disease is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Specifically, this revised application will define how the chemokine CXCL1 as well as it?s signaling receptor CXCR2 affects neuroinflammation, demyelination and remyelination in the JHMV and EAE models of neuroinflammation and demyelination. To accomplish this, we will use mice engineered in which i) astrocyte-derived expression of the chemokine CXCL1 is inducible following doxycycline (Dox) treatment and ii) CXCR2, a signaling receptor for CXCL1, is selectively ablated upon tamoxifen (4-OHT) treatment within oligodendroglia in adult mice. We will use these animals to build on both published data and extensive preliminary data to further define how CXCL1 affects disease by attracting neutrophils into the CNS as well as influencing OPC maturation. Similarly, we will characterize how targeted ablation of CXCR2 on oligodendrocytes affects neuroinflammation and remyelination. Results from these studies will provide additional clarity to the importance of the CXCL1:CXCR2 signaling axis in both disease progression and repair and may reveal these to be relevant targets for treatment of human demyelinating diseases such as MS.